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Highly pathogenic avian influenza A(H5N1) virus: Are we so far from a new pandemic?

While the COVID-19 pandemic is not yet behind our shoulders, due to the repeated appearance of new SARS-CoV-2 variants and subvariants, the highly pathogenic avian influenza (HPAI) A(H5N1) virus is being increasingly perceived as a global threat.
Go to the profile of Giovanni Di Guardo
Giovanni Di Guardo
Retired Professor of General Pathology and Veterinary Pathophysiology, University of Teramo, Faculty of Veterinary Medicine
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Since its first description in 1959 in Scottish poultry farms (1), the A(H5N1) virus was subsequently identified in 1996 in intensively reared ducks and chickens from China (2), with the first human infection case having been additionally reported in 1997.
 
Nowadays, approximately 1,000 disease episodes caused by HPAI A(H5N1) virus (mostly characterized by severe pneumonia and, occasionally, by encephalitis) have been ascertained in people on a global scale, with a 50% case-fatality rate and with 23 different Countries being also affected (3).
 
Within this framework, the recent migratory bird-driven spread of A(H5N1) virus clade 2.3.4.4b to a huge and progressively growing number of domestic and wild avian and mammalian host species from Eurasia, North and South America, up to the Arctic and Antarctica regions - including South American sea lions and a polar bear in Alaska (4,5) -, is of concern, according to the Scientific Community, the World Health Organization, the World Organization for Animal Health and the public health Authorities from many European and extra-European Countries. More in detail, the consistent viral neurotropism and neuropathogenicity (5,6), coupled with a high infection's lethality rate and the well-established propension of influenza viruses to undergo mutations (7) - especially at the level of haemagglutinin and polymerase genes -, are of crucial relevance, given the already threatened health and conservation status of several A(H5N1) virus-susceptible wildlife species.
 
Indeed, the aforementioned mutations have allowed, and continue still to allow, a successful pathogen's adaptation to a consistent and progressively growing number of avian and mammalian hosts, including species that are phylogenetically distant from each other. The last one in chronological order is represented by the ovine species, with a case of A(H5N1) viral infection having been recently reported in a sheep from Yorkshire (8).
 
Within such context, cattle are of significant concern, given their well-known susceptibility to HPAI A(H5N1) viral clade 2.3.4.4b. As a matter of fact, since the bovine mammary gland may be targeted by both avian and human origin viruses - with viral infectivity having been clearly shown in unpasteurized milk -, this could "accreditate" cattle as a further "mixing vessel" allowing the genetic reassortment and recombination between avian and human viruses, similarly to swine.
 
Cases of severe respiratory and neurological A(H5N1) viral disease have been also described in cats following the consumption of raw milk from infected cattle (9) as well as in farm workers from Texas, Michigan and other USA regions, in whom a bilateral conjunctivitis is commonly observed, sometimes accompanied by a febrile syndrome with mild respiratory signs (10).
Despite the hitherto available "absence of evidence" towards HPAI A(H5N1) virus interhuman transmission, the recently demonstrated susceptibility of mice and ferrets to a viral strain recovered from the conjunctiva of a patient in Texas should be viewed as another serious concern issue. Such experimentally challenged animals developed, in fact, a lethal systemic infection characterized by severe bilateral pneumonia and encephalitis (11).
 
Finally, since we are dealing with a zoonotic infection, in a similar manner to what happens with "emerging infectious diseases", whose proven or suspect origin lies for two thirds of them in one or more animal reservoirs, the main take-home messages for efficiently tackling and counteracting HPAI A(H5N1) virus spread among birds and mammals as well as from birds and mammals to humans, with special emphasis on interhuman transmission, may be summarized by the following key words:
Multidisciplinarity, intersectorial cooperation, predictive epidemiology, tracking of viral genetic mutations, open data and, last but not least, One Health.
 
 

References

  1. USA Centers for Disease Control and Prevention (CDC). 1880-1959 Highlights in the History of Avian Influenza (Bird Flu) Timeline.DOI: https://www.cdc.gov/bird-flu/avian-timeline/1880-1959.html.
  2.  USA Centers for Disease Control and Prevention (CDC). Emergence and Evolution of H5N1 Bird Flu. (2024).DOI: https://www.cdc.gov/flu/avianflu/communication-resources/bird-flu-origin-infographic.html.
  3.  USA Centers for Disease Control and Prevention (CDC). About Bird Flu. (2024).DOI: https://www.cdc.gov/flu/avianflu/communication-resources/bird-flu-origin-infographic.html.
  4. Huang P., Sun L., Li J., Wu Q., Rezaei N., Jiang S., Pan C. (2023). Potential cross-species transmission of highly pathogenic avian influenza H5 subtype (HPAI H5) viruses to humans calls for the development of H5-specific and universal influenza vaccines. Cell Discov. 9(1):58. DOI: 10.1038/s41421-023-00571-x.
  5. Di Guardo G. (2024). Central Nervous System Disorders of Marine Mammals: Models for Human Disease? Pathogens 13(8):684. DOI: 10.3390/pathogens13080684
  6. Bauer L., Benavides F.F.W., Veldhuis Kroeze E.J.B., de Wit E., van Riel D. (2023). The neuropathogenesis of highly pathogenic avian influenza H5Nx viruses in mammalian species including humans. Trends Neurosci. 46(11):953-970. DOI: 10.1016/j.tins.2023.08.002.
  7. McKie R. (2024). Next pandemic likely to be caused by flu virus, scientists warn. The Observer. DOI: https://www.theguardian.com/world/2024/apr/20/next-pandemic-likely-to-be-caused-by-flu-virus-scientists-warn
  8. Mahase E. (2025). H5N1: UK reports world's first case in a sheep. BMJ 388: r591. DOI : https://doi.org/10.1136/bmj.r591.
  9. Burrough E.R., Magstadt D.R., Petersen B., Timmermans S.J., Gauger P.C., Zhang J., Siepker C., Mainenti M., Li G., Thompson A.C., Gorden P.J., Plummer P.J., Main R. (2024). Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Domestic Dairy Cattle and Cats, United States, 2024. Emerg. Infect. Dis. 30(7):1335-1343. DOI: 10.3201/eid3007.240508.
  10. Garg S., et al. (2025). Highly Pathogenic Avian Influenza A(H5N1) Virus Infections in Humans. N. Engl. J. Med. 392(9):843-854. DOI: 10.1056/NEJMoa2414610.
Go to the profile of Giovanni Di Guardo
Giovanni Di Guardo (He/Him)
Retired Professor of General Pathology and Veterinary Pathophysiology, University of Teramo, Faculty of Veterinary Medicine

Born in Turin, Italy, on July. 04. 1958. Married on July. 12. 1987 with Letizia Curini, MD and father of two children, Cecilia (25-years-old) and Benedetta (24-years-old). Degree in Veterinary Medicine, cum laude, Bologna University, Faculty of Veterinary Medicine, December. 20. 1982. "Post-graduate Fellow", Bologna University, Faculty of Veterinary Medicine, Institute of General Pathology and Veterinary Pathological Anatomy, 1982-1985. State Veterinary Officer, Italian Ministry of Health, General Directorate of Veterinary Services, Rome, Italy, 1985-1987. "Assistant Veterinarian", Istituto Zooprofilattico Sperimentale (IZS) delle Regioni Lazio e Toscana, Rome, Italy, 1987-1993. "Chief Veterinary Pathologist", IZS delle Regioni Lazio e Toscana, Rome, Italy, 1993-January. 31. 2002. "Associate Professor", teaching "General Pathology and Veterinary Pathophysiology" (Academic Years 2001-2002, 2002-2003, 2003-2004, 2004-2005, 2005-2006, 2006-2007, 2007-2008, 2008-2009, 2009-2010, 2010-2011, 2011-2012, 2012-2013, 2013-2014, 2014-2015, 2015-2016, 2016-2017, 2017-2018, 2018-2019 and 2019-2020), as well as "Necropsy Techniques and Post-Mortem Diagnostic Pathology" (Academic Years 2001-2002 and 2002-2003), "Immunology" (Academic Year 2002-2003), "Cell Pathophysiology" (Academic Years 2003-2004, 2018-2019 and 2019-2020), University of Teramo, Faculty of Veterinary Medicine. Recipient of a unanimously positive/favourable evaluation, on behalf of the Examining/Evaluating Commission (composed by 5 distinguished Full Professors active in the concerned Disciplines, with one of them being a highly qualified foreign Member, namely Prof. Lluis Ferrer, from the Veterinary Faculty of the Universitat Autònoma de Barcelona, Barcelona, Spain), within "Abilitazione Scientifica Nazionale" (ASN) for "Full Professorship in Veterinary Pathology" (SSD 07/H2, VET/03) (ASN-2012; January. 09. 2014). Since January 05, 2021 officially retired from the position of Associate Professor of General Pathology and Veterinary Pathophysiology at the Veterinary Medical Faculty of the University of Teramo. Recipient of a unanimously positive/favourable evaluation, on behalf of the Examining/Evaluating Commission (composed by 5 distinguished Full Professors active in the concerned Disciplines), within "Abilitazione Scientifica Nazionale" (ASN) for "Full Professorship in Animal Infectious and Parasitic Diseases" (SSD 07/H3, VET/05) (ASN-2016-2018; March. 27. 2018). "Visiting Professor" and "Fulbright Scholar", in charge also of a research grant in "Comparative Oncology" from the Italian National Research Council (CNR), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA, October 1987-January 1988. "Visiting Scientist", Department of Agriculture and Rural Development for Northern Ireland (current denomination: Agri-Food and Biosciences Institute for Northern Ireland), Veterinary Sciences Division, Stormont, Belfast, Northern Ireland (UK), 4-14. December. 1991 (first visit) and 14-18. April. 2008 (second visit), carrying out research activity on the pathology and pathogenesis of infectious disease conditions affecting free-living sea mammals (cetaceans, in particular), with special emphasis on Morbillivirus infections. "Diplomate", European College of Veterinary Pathologists (Dipl., ECVP), 1995-to date. Member of the "Fondazione Cetacea" Scientific Commission, Riccione, Italy, 1997-to date. Member of the "Consulting and Operative Animal TSE Unit for Latium and Tuscany Regions", 1997-2002. Member of the "Italian TSE National Surveillance Group", 1998-2002. Member of the "Technical and Scientific Committee for the Regional Plan of Genetic Selection for Resistance to Transmissible Spongiform Encephalopathies" (Abruzzo Region, Department of Health and Welfare), January 2003-to date. "International Training Expert", EU Phare Project 2003 on "TSE Control in Poland - Part 2", Training Course on "Control and Diagnostic Methods of Transmissible Spongiform Encephalopathies (TSE)", Warsaw (Poland), 3-7. April. 2006. Italian Delegate, Scientific Committee, 59th, 60th and 64th "International Whaling Commission" (IWC) Annual Conferences. Member/Component of the "ACCOBAMS Task Force for Special Cetacean Mortality and Stranding Events", 2008-to date; Scientific Expert, Group on "Cetacean Emerging and Recurring Diseases" (CERD), "Scientific Committee", "International Whaling Commission" (IWC), 2007-to date. Member/Component of the "EFSA Expert Database" (European Food Safety Authority, EFSA), June 2010-to date. External Scientific Member/Component of the "Body/Committee for Animal Welfare" of the Italian National Institute of Health (since 2015). Member/Component of the "National Experts' Committee of the Italian Marine Mammal Stranding Network" (following the official, joint nomination achieved on behalf of the Italian Ministry for the Environment and by the Italian Ministry for Health) (since 2016). Member/Component of the Working Group on the "Reduction of the list of specified risk materials from small ruminants, sheep and goat", Italian National Health Council (Sections III & IV); official invitation made by the President of the Italian National Health Council, as well as by the two Presidents of Sections III & IV of the Council itself, January 2017-. Member/Component of the "Histology Study Committee" within the "Italian Association of Veterinary Laboratory Diagnosticians" (S.I.Di.L.V.), September 2017-. Enrolled into the "Italian National Registry" of the "Experts" ("Scientific Discipline Experts"), handled/held by the "Italian National Agency for the Evaluation of University and Scientific Research" (ANVUR), February 2019-. Member of several International and National Scientific Societies, as well as of the Scientific Committee of the "Italian Association of Veterinary Pathology" (AIPVet) and of the Scientific Committee of the "Italian Society for Preventive Veterinary Medicine" (SIMeVP) (2007-2010). Member/Component of 3 (three) distinct PhD Thesis International Examining Boards/Committees, University of Las Palmas de Gran Canaria, Faculty of Veterinary Medicine, Las Palmas, Gran Canaria, Canary Islands, Spain; International and National (PRIN) Research Project evaluator, as highlighted - among others - by the peer review evaluation activities conducted on a number of transnational research projects submitted within the second call (2011) in the framework of the "EMIDA (Emerging and Major Infectious Diseases of Animals) ERA-Net" (European Union, EU) network, as well as on a number of international research proposals presented both in the context of the "7th Framework Programme (FP7; 2007-2013) for Scientific Research of the European Union" (EU "People" Programme/Action) and in the framework of the "EXPRO Tender", under the umbrella of the "Czech Science Foundation". External Scientific Member of the "Organism for Animal Welfare", Italian National Institute of Health, November 2014-to date. Member/Component of the Scientific Research Board/Committee of the University of Teramo (as Delegate/Representative of the Veterinary Medical Faculty), June 2013-to date. Member/Component of the "Examining and Certifying Board for Professional Licensing/Qualification as a Veterinarian" (University of Teramo, Faculty of Veterinary Medicine, Years 2007 and 2019, June and November Sessions). "Scientific Editor" (for "Veterinary Pathology") and Member of the Editorial Board of the international Journal "Research in Veterinary Science", September 2010-to date; Member of the Editorial Board of the international Journal "Journal of Biological Regulators and Homeostatic Agents", March 2015-to date; Member of the Editorial Board of the international Journal "Pathogens", November 2019-to date; Member of the Editorial Board of the scientific Journal "Tabaccologia", March 2020-to date; Member of the Editorial Board of the scientific Journal "Ittiopatologia", 2007-to date; past-Member of the Editorial Board of the scientific Journal "Aggiornamenti di Medicina e Chirurgia". Scientific coordinator of a number of research projects concerning both animal TSEs and cetaceans' pathology, all financially supported by the Italian Ministry of Health, by the Italian Ministry for Education, University and Research (MIUR) and by the Italian Ministry for the Environment. Author or coauthor of over 500 scientific publications, 190 of which published in international peer-reviewed Journals (see "ad hoc" publications' list). Main research interests concern infectious disease conditions in animals and man, with particular emphasis on TSE pathogenesis (more specifically, on sheep and goat scrapie pathogenesis) and on sea mammals' pathology (more in detail, on free-living cetaceans' pathology).

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